The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

Hale Tunbak, Rocio Enriquez-Gasca, Christopher H. C. Tie, Poppy A. Gould, Petra Mlcochova, Ravindra K. Gupta, Liane Fernandes, James Holt, Annemarthe G. Veen, Evangelos Giampazolias, Kathleen H. Burns, Pierre V. Maillard and Helen M. Rowe ()
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Hale Tunbak: Queen Mary University of London
Rocio Enriquez-Gasca: Queen Mary University of London
Christopher H. C. Tie: University College London
Poppy A. Gould: Queen Mary University of London
Petra Mlcochova: University of Cambridge
Ravindra K. Gupta: University of Cambridge
Liane Fernandes: Queen Mary University of London
James Holt: Queen Mary University of London
Annemarthe G. Veen: The Francis Crick Institute
Evangelos Giampazolias: The Francis Crick Institute
Kathleen H. Burns: John Hopkins University School of Medicine
Pierre V. Maillard: Queen Mary University of London
Helen M. Rowe: Queen Mary University of London

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex.

Date: 2020
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DOI: 10.1038/s41467-020-19170-5

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